We have began to use TFP5 to study its therapeutic role in PD. Parkinsons disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously, we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer's disease (AD). Here, we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro, rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+),in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflamation and apoptosis. Here, we show selective inhibition of Cdk5/p25 hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson's disease. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptides efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, we show that peptide i.p. injections in these mice decrease Cdk5 activity, tau, neurofilament-M/H hyper phosphorylation, and restore synaptic function (LTP) and behavior (i.e., spatial working memory). It is noteworthy that TFP5 does not inhibit endogenous Cdk5/p35 activity, or other Cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive Cdk5. As a proof of concept, we have demonstrated that the peptide, injected into an AD model mouse overexpressing Cdk5/p25 (P25Tg mice), specifically targets the hyperactive kinase, reduces or eliminates AD pathology, and restores normal behavior. We suggest that the peptide may serve as a potential therapeutic candidate for those neurodegenerative disorders that overexpress p25, the hyperactive activator. Currently we have further extended these neuroprotective effects of Peptide TFP5/TP5 in Parkinson's disease, MPTP and 6-hydroxy dopamine animal models. A manuscript entitled Peptide (TFP5/TP5), derived from Cdk5 activator P35, provides neuroprotection and rescues phenotypes in the MPTP model of Parkinson's disease accepted in Molecular Biology of Cell. The editor of the journal made the following comments. This is a major advance that should be considered for clinical applications. In light of these studies presented in this manuscript, I am recommending this work be considered for MBOC Highlights and presentation to the general public as an example of how basic research in cell biology advances our understanding of human life and health. This is an excellent extension of the neuroprotective role of the cdk5 inhibitory peptide (TFP5/TP5) to prevent the symptoms of Parkinson's disease. This is a major advance that should be considered for clinical applications. I recommend publication as is, no revisions required. We believe TFP5 acts on multiple pathways inhibiting hyper activation of Cdk5 and other kinases involved in inducing neuropathologies to reduces / prevents neurodegeneration and extends life.